Abnormalities in mood, anxiety, and cardiac regulation are common in psychiatric disorders. Deficits in vagal tone, particularly loss of parasympathetic cardiac regulation, are associated with risk for cardiovascular disease (CVD). These clinical and cardiac deficits are found in major depressive disorder (MDD). Vagal nerve stimulation (VNS) is an FDA approved treatment for MDD that modulates shared brain circuitry implicated in mood/anxiety and cardiac regulation. Although brain circuitry for mood/ anxiety and autonomic nervous system (i.e. cardiac regulation; ANS) regulation are overlapping, VNS modulation of ANS has not been examined in association with mood response. Further, the primary method for VNS is implanted VNS and we are proposing the use of transcutaneous VNS (tVNS) as a low risk, non-invasive, and inexpensive alternative intervention. We will identify whether acute tVNS effects on brain circuitry in MDD (an extreme of these mood and arousal traits) are associated with modulation of mood, anxiety and vagal tone and whether tVNS can modulate the brain's response to stress (a trigger for MDD). Twenty MDD premenopausal (ages 25-40) unmedicated women with recurrent MDD will undergo an fMRI mild visual stress challenge task that we have previously shown activates central ANS. In tandem, they will have ECG evaluation, out of which the high frequency component of the R-to- R interval variability (HF-RRV, i.e., parasympathetic cardiac regulation) will be assessed. The stress challenge will precede and follow a 20 minute session of tVNS also during fMRI scanning and in tandem with ECG. Women will be scanned twice within 2-3 days to assess acute tVNS effects compared to active sham at baseline and under mild stress. We hypothesize there will be increases in vagal tone following tVNS and decreases in mood and anxiety symptoms. We further hypothesize that tVNS will impact brain activity in specific limbic and cortical regions associated with negative affect (mood and anxiety) and HF-RRV (parasympathetic) regulation that we previously identified in MDD women. Further, we hypothesize that these changes will be related to one another. In the proposed study, we will characterize in MDD women: 1) neural circuitry modulated by tVNS, 2) acute effects of tVNS on HF-RRV and mood and anxiety symptomatology; and 3) associations between changes in brain activity, ANS function and mood. The combination of imaging and stereotaxic brain stimulation is a powerful approach for developing novel treatment paradigms. The work will advance our understanding of the shared pathophysiology of mood and cardiac regulation and how this may contribute to symptom alleviation using a less invasive form of VNS that may have wider applications. Thus, this project has the ultimate potential to 1) discover a novel treatment for comorbid MDD and CVD; 2) decrease the risk of CVD in MDD patients; and 3) elucidate the neurobiologic circuitry and physiology associated with tVNS therapeutic response. Finally, the work is relevant for all patients with mood and cardiac dysregulation, furthering individualized medicine for comorbid psychiatric disorders with CVD.